A major hurdle in the realm of pharmaceutical and medicinal chemistry is the ability to deliver biologically effective drugs that are soluble in a carrier and chemically stable when presented to an aqueous environment. One way to solubilize and stabilize medicinal agents is to chemically modify them or conjugate them to another molecule to alter the solubility profile and chemical stability in a particular solvent. Conjugates of active drugs, often referred to as prodrugs, include chemical derivatives of biologically-active parent compounds that are converted into the parent compounds in vivo. The release of the active parent drug from the prodrug conjugate may occur as the result of processes such as hydrolysis or enzymatic cleavage. The rate of release is influenced by several factors, including the type of chemical bond joining the active parent drug to the conjugate moiety.
Several technologies have been developed to facilitate the delivery of poorly soluble and insoluble compounds to patients. Examples of technologies specifically designed to solve solubility problems include complexing agents, nanoparticles, microemulsions, solubility enhancing formulations, prodrugs, and novel polymer systems. As a specific example, a water-soluble moiety (e.g., polyethylene glycol, polyglutamate, or polymer) can be conjugated to a drug to increase solubility and circulation life.
5-azacytidine is a chemical analogue of cytidine with antineoplastic activity. 5-azacytidine is unstable in buffer and plasma, with an average terminal half-life of 1.50±2.30 hours in clinical plasma samples. In vitro, a 20% loss of 5-azacytidine occurs even at −60° C. after 4.5 days storage, and a 10% loss occurs within 0.5 hours when stored at room temperature.
An elaidic ester of 5-azacytidine has been developed in an effort to improve chemical stability of 5-azacytidine. The ester prodrug can be made by conjugating elaidic acid to the 5′ position of the sugar of 5-azacytidine. 5-azacytidine elaidic acid esters have a significantly better plasma stability profile than 5-azacytidine itself. For example, when held in blank human plasma matrix at room temperature for at least 4 hours under the experimental conditions, 94% percent of the initial 5-azacytidine elaidic acid ester can remain (compared to an initial amount) with no significant degradation products in the post-extract supernatant, after precipitation of plasma proteins. Furthermore, the ring-opening of the 5-azacytidine-moiety or other degradation of the compound is significantly reduced when the elaidic acid side chain is attached to 5-azacytidine.
In addition to providing chemical stability, conjugation of 5-azacytidine with elaidic acid can bypass the transport mechanism for nucleosides, which can be one source for drug resistance. The elaidic acid ester conjugate can also reduce the likelihood of deamination by cytidinedeaminase.
Similarly, an elaidic acid ester prodrug of gemcitabine has also been previously developed. However, clinical trials did not show any difference in survival in patients with pancreatic cancer between the elaidic acid prodrug and gemcitabine.
Vitamin E presents another method for functionalizing therapeutic agents. There are two main forms of vitamin E: tocopherols and tocotrienols. Tocotrienols represent a very important part of the vitamin E family. However, most of the vitamin E research has focused on α-tocopherols, and only 1% of vitamin E studies have investigated tocotrienols.
Some of the isoforms of tocopherols and tocotrienols have been reported to have antiproliferative activity. Indeed, tocotrienols have shown an activity against a number of different cancers, including breast, leukemia, liver, pancreas, and prostate, amongst others. It should be noted that γ-tocotrienol appears to be the most frequently tested for antineoplastic activity, but that formal ranking of relative biopotency of tocopherols and tocotrienols for suppression of cell growth and induction of cell death of specific vitamin E isoforms display a consistent relationship corresponding to δ-tocotrienol≥γ-tocotrienol>α-tocotrienol>δ-tocopherol>>γ and α-tocopherol.
α-Tocopheryl phosphate (α-TP), a water-soluble analogue of α-tocopherol, is found in humans, animals, and plants. α-TP is resistant to both acid and alkaline hydrolysis and may exert its own function in this form in vivo. α-TP appears to be taken in and hydrolyzed readily to α-tocopherol in cultured cells and in mice. This hydrolysis of α-TP to α-tocopherol most likely is mediated by a phosphatase. α-TP has been found to be pro-apoptotic and mixed tocopheryl phosphates have shown little toxicity in formal toxicology studies.
Nucleosides typically need to be metabolized to nucleotides, i.e., phosphorylated nucleosides, to be effective as therapeutics. A rate limiting step in nucleotide synthesis is generation of the monophosphate (MP). For example, gemcitabine is phosphorylated to the MP by deoxycytidine kinase (dCK) and dCK “deficiency” can be responsible for acquired and intrinsic resistance. While desirable, delivery of MP-nucleosides to cells has been a challenge in medicinal chemistry because phosphates are acidic and negatively charged at physiologic pH, and phosphohydrolases rapidly convert MP-nucleosides to corresponding nucleosides. Furthermore, because many nucleosides are poorly phosphorylated, intracellular delivery of a monophosphorylated nucleoside with low toxicity and good affinity to polymerases is a challenge that has been difficult to surmount.
There is a need for therapeutic agents that can bypass major mechanisms of tumor resistance while providing enhanced stability and activity. The present disclosure seeks to fulfill this need and provides further related advantages.